Bovine Respiratory Syncytial Virus (BRSV) is now recognized as an important etiologic agent in the Bovine Respiratory Disease Complex (BRDC). Disease is characterized by rapid breathing, coughing, loss of appetite, ocular and nasal discharge, and elevated temperatures. In an acute outbreak, death may follow within 48 hours of onset of symptoms.
BRSV infects cattle of all ages, including nursing calves. BRSV is considered the most common viral pathogen in enzootic pneumonia in calves, and has also been associated with pulmonary emphysema among newly weaned calves. Thus, there is a need for effective prophylaxis against this virus in cattle and dairy herds.
Establishing protective immunity against BRSV is problematic. As in some other virally-mediated diseases, the levels of serum antibodies against BRSV do not necessarily correlate with protection against disease. This phenomenon may reflect a role for locally produced IgA directed against BRSV (Kimman et al., J. Clin.Microbiol. 25: 1097-1106, 1987), and/or a requirement for cell-mediated immunity to mount an effective defense against this virus. Establishing protective immunity in nursing calves presents additional obstacles, since maternal antibodies to BRSV may deplete the injected immunogen and effectively neutralize the vaccine. Finally, the inconvenience and expense of multiple vaccinations makes a single-dose vaccine desirable. Thus there is a need in the art for one-dose BRSV vaccine formulations that elicit a vigorous and multi-faceted immune response.
The standard administration regimen for prior art BRSV vaccines is two doses (Stott et al., J. Hyg.Camb. 93: 251-261, 1984; Thomas et al., Agri-Practice 5: 1986; and Syvrud et al., Vet.Med. 83: 429-430, 1988; Veterinary Pharmaceuticals & Biologicals, Edition 8 1993/94, pp. 484, 740-741, 956-960, 982-983.) As shown in Kucera et al. (Agri-Practice, Vet.Med., Vol. 78, October 1983, pp. 1599-1604, 1983), a single experimental BRSV vaccination induced relatively low levels of serum neutralization (SN) antibody titer to BRSV, whereas two doses of the vaccine elicited 1:10 to 1:320 SN antibody titers. Furthermore, in herds apparently exposed to BRSV during field trials, approximately 48% of non-vaccinated animals required treatment for respiratory disease, compared with 27% and 21% among single-dose and double-dose vaccinates, respectively. However, the causative agent for respiratory disease in the field trials was not conclusively shown to be BRSV. Also, it was noted that a single-dose vaccine did not appear to be very immunogenic. Later evaluations concluded that two doses of this vaccine would be essential to obtain good protection (Bovine Vet.Forum 1: No.2 pp. 2-16, 1986; Syvrud, et al., Vet.Med. 429-430, 1988).
European Patent Application No.129,923 (published Feb. 1, 1985 and issued as a patent Jul. 9, 1988) describes a method of preparing a live BRSV vaccine that involves dissolving the live vaccine in an inactivated vaccine containing one or more antigens (particularly inactivated influenza virus) formulated as an oil-in-water emulsion. A serological response was obtained in young animals still having maternal immunity. The application also describes a modified-live preparation including BRSV and adjuvant. However, no data were presented on the protective efficacy of any BRSV vaccine against BRSV challenge.
One object of the invention is to provide an effective vaccine against BRSV that elicits protective immunity and prevents disease caused by this virus.
A further object of the invention is to provide an adjuvant suitable for use in a BRSV vaccine, wherein the adjuvant enhances the immunogenicity of the virus so as to elicit protective immunity after a single dose of the vaccine.